Current Good Manufacturing Practice (cGMP) is a key factor for manufacturers/ industries to produce good quality, safe and affordable products, especially in respect of consumables like food products. 

The cGMP guidelines as issued by the National Agency For Food and Drug Administration and Control (NAFDAC) are a set of technical principles and recommendations used in processing food products in order to guarantee that they are safe and suitable for consumption, and to prevent contamination or adulteration. They are also sometimes called “good processing practices” or “good fabrication practices”.

cGMP guidelines are established to satisfy regulatory requirements as well as maintain the high quality standards of products.

This guideline has been developed to highlight good manufacturing practices that should be followed by manufacturers, operators and employees to maximally assure the production of safe and sanitary products at all times. 

The guidelines offer suggestions for measures and precautions that should be taken regarding employee health, food handling practices, appearance, personal hygiene, plant procedures, plant and equipment design, maintenance, and sanitation. The document also offers some examples of GMP documentation, which has been identified as one of the main shortcomings in implementing food safety and food quality management systems.

It is important that every employee is made knowledgeable and aware of the necessity of adhering to these guidelines at all times. The guidelines need to be re-emphasized by the manufacturer on a regular basis and that regular assessment and review of how well the guidelines are being followed should be conducted by management.

We will thus be taking a look into the notable provisions and regulatory requirements of these guidelines 

What is the scope of the cGMP guidelines?

These guidelines apply to food manufacturers/industries and covers all activities undertaken from the point where raw materials are received, through processing, storage and distribution of final products.

What are the provisions of the guidelines regarding the application of good manufacturing practices?

-The guidelines state that good manufacturing practices should be applied with sanitary criteria in mind. 

-As there will always be situations where specific requirements do not apply, the key is to assess whether a recommendation is “necessary” from the standpoint of food safety and suitability. 

-The application of Good Manufacturing Practices also requires reassessing the potential risk of each food hazard in food processing. 

-While less severe hazards or hazards not very likely to occur will probably not need to be analyzed in an HACCP plan, they must be addressed within the framework of GMP. 

-Thus, to apply good manufacturing practices, business operators will also need to perform a hazard analysis for each product or type of process, and for each new product, even though they are not implementing the HACCP.

-Good Manufacturing Practices and the HACCP system are interrelated and interdependent: application of GMP requires familiarity with the principles of the HACCP system to ensure a comprehensive approach to food safety.

What are the provisions of the guidelines regarding organization and personnel? 

-There shall be an adequate number of personnel, as determined by the company, at all levels having appropriate education, knowledge, training, experience, skill and capabilities or a combination thereof relevant to their assigned functions, in good mental and physical health to be able to execute their duties.

Organization, Qualification, and Responsibilities

• The organizational structure of the company should be such that the production and the quality assurance/quality control functions are headed by different managers/heads, neither of whom shall be reporting to the other. Each shall be given full authority and facilities necessary to execute their duties effectively.

• The production manager/head shall be adequately trained and/or shall possess good practical experience in the field of food manufacture or any other related field, and managerial skill, which will enable him/her to perform the function effectively. The production manager shall have full authority and responsibility to manage production of food products. Additionally, the production manager shall have other responsibilities, which he shall share with the quality assurance/quality control manager and the person responsible for engineering.
• The quality assurance/quality control manager/head shall have adequate training and practical experience, which will enable him perform his function effectively. The quality assurance/quality control manager/head shall have full authority and responsibility in all quality assurance and quality control duties such as establishment, verification and implementation of all quality control procedures.
• The quality assurance/quality control unit shall be entrusted with the responsibilities and authority to:

i.Approve/reject all components – raw and packaging materials, labeling materials, as well as bulk and finished products.

ii.Approve/reject product manufactured or packed or, held under control by a third party manufacturer.

iii.Approve/reject procedures, which have impact on the product quality or product specifications.

iv.Review production records and quality control records.

v.Support monitoring and controlling the manufacturing environment, plant cleanliness, production validation, calibration, training of personnel, approve supply of materials and contract parties, protect products and materials against spoilage and deterioration and the maintenance of records.

• The quality assurance/quality control manager/head shall share responsibility with the production manager/head for establishing and authorizing written procedures.

• The production manager/head shall have full authority and responsibility to manage the production of products covering all aspects of personnel, area, equipment and records.

• The production manager/head shall share with the quality assurance/quality control manager/head the responsibility of product quality and authority in the aspects specified in the guidelines.

• The duties of every employee shall be clearly defined, communicated and well understood, and shall be within an employee’s capacity to perform.

Training

• All employees who are directly engaged in the manufacturing, processing, packaging and holding of food and food products shall be trained in the particular operations they perform in accordance with the principles of current Good Manufacturing Practice.

• Training shall be conducted by qualified personnel.

• Training in Good Manufacturing Practices shall be on a continuing basis and with adequate frequency to assure that employees remain familiar with the Good Manufacturing Practice requirements relevant to their functions.

• Training in Good Manufacturing Practices shall be in accordance with written programs approved by the production and quality control managers/heads.

• Records of personnel training in Good Manufacturing Practices shall be maintained.

• After training, the consequential employees’ performance shall be appraised to determine their further training needs.

What are the provisions of the guidelines on buildings and facilities?

Buildings

-Buildings should be located, designed, constructed, adapted and maintained to suit the operations carried out in them and to facilitate the protection of materials and products from contamination or deterioration. 

-Equipment should be designed, constructed, adapted, located and maintained to suit the processes and products for which it is used and to facilitate protection of the materials handled from contamination or deterioration.

Location

a.The first thing to consider is where to locate a food processing establishment. The surroundings must be taken into consideration to ensure that they do not have an adverse effect on the food processed. Facilities should not be located near areas considered adverse or harmful, for example, sanitary landfills, areas subject to flooding, industrial activities that pose a threat of contaminating food, or other sources of contamination. Generally, a minimum distance of 30 meters from potential sources of contamination is recommended.

 b.Establishments should be adequately fenced round with blocks to prevent external interference and shall be located away from:

i.Environmentally polluted areas and industrial activities, which pose serious threat of contaminating food;

ii.Areas with excessive dust, foul odours, smoke, airborne microbial and chemical contaminants, such as quarry sites, abattoirs, sewage treatment or oxidation lagoons, animal habitats, dusty roads, soak-away pits, cemetery etc.

iii.Areas subject to flooding unless sufficient safeguards are provided such as channels, drainages etc.

iv.Areas prone to infestation of pests;

v.Areas where wastes, either solid or liquid cannot be removed effectively.

What are the general provisions of the guidelines regarding premises?

General Requirements for Premises

Premises should:

• provide sufficient space to suit the operations to be carried out;
• allow an efficient flow of work;
• provide suitable internal storage areas;
• facilitate effective communication and supervision;
• be sited with due regard for the provision of services needed and to avoid contamination from adjacent activities. In existing premises, effective measures should be taken to avoid such contamination;
• Be maintained in a good state of repair. The condition of buildings should be reviewed regularly, and repairs effected where necessary. Special care should be exercised to ensure that building materials of construction, repair or maintenance operations are not allowed to adversely affect product quality or integrity.

Grounds

• Grounds shall be constructed and maintained to protect against weather, flood, ground seepage, and the access and harboring of vermin, rodents, birds, insects or other animals.

• If the plant grounds are bordered by grounds not under the operator’s control, care shall be exercised by conducting inspection, extermination, or other means to exclude pests, dirt, and filth that may be a source of food contamination.

1. The grounds about a food plant under the control of the operator shall be kept in a condition that will protect against the contamination of food.

1. The methods for adequate maintenance of grounds shall include, but are not limited to:

i.Good housekeeping. Properly storing equipment, removing litter and waste, and cutting weeds or grass within the immediate vicinity of the plant buildings or structures that may constitute an attractant, breeding place or harborage for pests.

ii.Providing and properly operating systems for waste treatment and disposal designed and constructed in an appropriate manner so that they do not constitute a source of contamination of areas where food is exposed.

What are the provisions of the guidelines regarding sanitation and hygiene?

Personnel

-The plant management shall define its policy and document its procedures on sanitation and personnel hygiene and take all reasonable measures and precautions to ensure the following:

–Disease Control.

1. Persons directly involved in the manufacturing, food processing or packing should be fit and capable of discharging their duties effectively.

1. Any personnel who, by medical examination or supervisory observation, is shown to have, or appears to have, an illness, open lesion, including boils, sores, or -infected wounds, or any other possible source of microbial contamination shall be excluded from any food handling/contact operations until the condition is corrected.
2. Illnesses, symptoms and injuries that should be immediately reported by employees to management so they can be examined by a doctor include:

• jaundice (yellowing of skin and eyes),

• diarrhea,
• vomiting,
• fever,
• sore throat with fever,
• visibly infected skin lesions (boils, cuts, etc.),
• discharges from the ear, eye or nose.

There shall be established/documented procedures for disease control including specific instruction for all personnel to report such health conditions to their supervisors.

Monitoring of personnel

– The business should have a set procedure for monitoring the personal health status of employees that includes, among other things:

i.Keeping track of employees’ health through health files for each employee where all health-related events are recorded.

ii.Requiring all persons or visitors who enter processing rooms to first fill out a form on their health status so as to prevent food contamination.

iii.Excusing food handlers with diarrhoea or other type of digestive illnesses from work because, even if they are not in contact with food, their use of toilet facilities among others may lead to contamination of other employees.

iv.Use of liquid soap in toilet facilities to prevent cross-contamination that can occur when bar soap is used. 

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Provisions for Contract Manufacturing of Finished Pharmaceutical Products

In Nigeria, members of the general public and especially organizations intending to engage in the manufacture of finished pharmaceutical products via contract manufacturing arrangements are expected to comply with a set of regulatory requirements put in place by the relevant agencies.

These regulatory requirements, put in place by the National Agency For Food and Drug Administration and Control (NAFDAC) and effective since the 3rd of February 2021, will be the focus of this article .

What are the implications of the NAFDAC Guidelines on Contract Manufacturing Of Finished Pharmaceutical Products in Nigeria?

The implications of the NAFDAC are that :-

– No regulated product should be manufactured, imported, exported, advertised, sold or distributed in Nigeria unless it has been registered in accordance with the provisions of the Food, Drugs and Related Products Act and accompanying guidelines. 

– A drug product should not be manufactured in Nigeria unless the facility has been inspected, found to comply with good manufacturing practices and an authority to manufacture pharmaceutical products is issued by NAFDAC.

– The NAFDAC Guidelines prescribe the minimum requirements to be met by parties wishing to engage in contract manufacturing of pharmaceutical products i.e. human & veterinary medicines, biologics, herbal medicine and nutraceuticals as well as medical devices

What are definitions of terms most commonly used by the guidelines?

The definitions of terms most commonly used in the guidelines are as follows :-

– Contract Facility :- A site where one or more manufacturing operations take place on behalf of the contract giver.

– Contract Giver :- A legal entity who has legal ownership of the finished product and who will be applying to NAFDAC for marketing authorization or entity that orders the conduct of a component of manufacturing to be carried out on their behalf by another entity.

– Contract Manufacturer/Contract Acceptor :- An entity that engages in GMP activities, including implementation of oversight and controls over the manufacture of drugs to ensure quality of other parties.

– Contract Manufacturing :- Manufacturing by a contract manufacturer/contract acceptor on behalf of the contract giver.

– Good Manufacturing Practice(GMP) :- That part of quality assurance which ensures that pharmaceutical products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by their marketing authorizations. It ensures that pharmaceutical products are manufactured so that they do not place the populace at risk.

– Manufacturing :- Includes processing, packaging, holding, labeling operations, testing and quality unit operations.

– Quality Agreement :- A comprehensive written agreement between parties involved in the contract manufacturing of pharmaceutical products that defines and establishes each party’s manufacturing activities in terms of how each will comply with GMP.

What are the principles guiding contract manufacturing agreements?

Some of these principles include the following :

– A manufacturer may perform all operations and activities or may engage an outside party or parties to perform some or all of the operations and activities under contract. NAFDAC shall allow product owners/manufacturers to contract some of these operations to any contract facility as defined above.

– Contract production and any other activity covered by GMP that is outsourced must be correctly defined, agreed and controlled in order to avoid misunderstandings that could result in a product or work or analysis of unsatisfactory quality.

– All arrangements for contract manufacturing including technology transfer and any proposed changes in technical or other arrangements, should be in accordance with the marketing authorization for the product concerned.

– Contract manufacturing may be undertaken only by a manufacturer who holds a valid manufacturing authorization.

What are the types of contract facilities under these guidelines?

The NAFDAC has classified contract manufacturing facilities into 2 groups for proper definition of the scope of operations and effective regulation as follows :-

– Full Contract Manufacturing Facilities (FCMF) : These are establishments that do not have any product registered by NAFDAC and are only involved in contract manufacturing operations for other parties.

– Partial Contract Manufacturing Facilities (PCMF) : These are establishments that are holders of market authorizations issued by NAFDAC for manufactured and are also involved in commercial contract manufacturing operations for other parties.

What are the responsibilities of parties involved in contract manufacturing under the guidelines?

Contract Manufacturing Parties

– Each party engaged in the manufacture of a drug is responsible for ensuring compliance with GMP for the manufacturing activities it performs.

– The responsible person designated by the contract giver should be party to approving or rejecting pharmaceuticals products manufactured by the contract facility, including final release except if such responsibility is otherwise established in the quality agreement.

Contract Giver

– The Pharmaceutical Quality System (PQS) of the contract giver should be include the control and review of any outsourced activities.

– The contract giver is responsible for :-

a). Assessing the legality, suitability and competence of the contract acceptor to successfully carry out the work or tests required.

b). Approval for contract activities

c). Ensuring by means of the contract that the principles of GMP incorporating QRM principles are followed to include the implementation of oversight and controls over the manufacture of pharmaceuticals to ensure quality & management of risk.

Contract Manufacturer/Acceptor

– The contract acceptor must have adequate premises, equipment, knowledge, experience and competent personnel to satisfactorily carry out the work ordered by the contract giver.

– The contract acceptor should ensure that all products or materials delivered to the facility are suitable for manufacturing of finished pharmaceutical products.

The Contract

– All arrangements for production and analysis must be in accordance with the marketing authorization and agreed by both parties.

What are the considerations required by the guidelines in documenting GMP activities in quality agreements?

– A quality agreement describes the contract giver’s and the contract acceptor’s roles and manufacturing activities under GMP.

– A well-written quality agreement should use clear language, define key manufacturing roles and responsibilities and establishes expectations for communication and providing key contracts for both parties.

– It will specify which products and/or services the contract giver expects from the contact acceptor and who has final approval for various activities.

– Quality agreements should state manufacturing services provided by contract facilities will comply with GMP.

Guidelines For The Importation of Active Pharmaceutical Ingredients (APIs) in Nigeria

The Guidelines for the importation of Active Pharmaceutical Ingredients (APIs) as released by the National Agency For Food and Drug Administration and Control (NAFDAC) is intended to provide guidance on the process for obtaining permits for  Active Pharmaceutical Ingredients (APIs) by Importers, Distributors, Brokers, Marketing Authorization Holders (MAH) who import or act as site for physical importation of APIs for own use or distribution, re-labellers, re-packers and other end users (e.g. educational, health and research institutions) in Nigeria.

This document is also intended to provide guidance for the control of APIs locally manufactured and distributed or exported out of the country.

API should not be imported into Nigeria unless the Finished Pharmaceutical Products (FPP) manufacturers, marketers, re-labelers, re-packers and other end users (e.g. Educational, health and research institutions) has been duly issued a Permit or Authorization to do so.

What are the definitions and abbreviations of important terms under the guidelines?

API(s) – Active Pharmaceutical Ingredient(s)

CTD – Common Technical Document

DS – Drug Substance

ASMF (DMF) – Active Substance Master File (Drug Master File)

LOA – Letter of Access / Authorization

FPP – Finished Pharmaceutical Product

MA – Marketing Authorization

MAH – Marketing Authorization Holder

Active Pharmaceutical Ingredient (API) or Drug Substance (DS)

– A substance used in a finished pharmaceutical product (FPP), intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure,  mitigation, treatment or prevention of disease, or to have direct effect in restoring,  correcting or modifying physiological functions in human beings.

Drug Master File (DMF)/Active Substance Master File (ASMF)

-A document containing complete information of an Active Pharmaceutical Ingredient or  finished drug dosage form. The drug manufacturer must include adequate information or data to demonstrate that the drug substance used for particular drug of interest will not in any way affect the safety and efficacy of the drug. The DMF contains complete and factual information on drug product chemistry, manufacture, stability, purity, impurity profile, packaging and the GMP of any human drug product. Drug Master Files consist of two parts namely open and closed parts.

What is the scope of these guidelines?

These guidelines apply to the following:

-All Drug Substances (DS) or Active Pharmaceutical Ingredients (APIs) that fall within the definition of APIs as given in this document whether manufactured locally, imported, exported, marketed, repackaged, relabeled, distributed, sold or used in the manufacture of drug products, for new products or generics in Nigeria except those materials indicated under exemption from these guidelines.

-Local manufacturers of Finished Pharmaceutical Products (FPPs) in Nigeria authorized by the Agency and intending to import APIs for manufacture of their products. 

-Applicants who import APIs solely for the purpose of sale and distribution.

-Applicants who hold wholesale authorization for distribution and sale of APIs but are not direct importers of APIs (DMF not required).

-Applicants who are manufacturers of APIs (local or foreign) that export, distribute or import APIs into Nigeria.

-Applicants or Institutions who import APIs for the purpose of Research and Development (R&D).

-Brokers who import APIs for clients.

What is the application method for API Importation permits under the Guidelines?

Applicants regarded as API manufacturers, FPP manufacturers, MAHs, Importers, Brokers, Exporters, Educational, Research or Health institutions; should submit DMF or equivalent documentation for API(s) for which permit is sought either for the purpose of distribution or to be used in the manufacture of or research into:-

-Investigational medicinal products

-New drug applications

– Abbreviated new drug applications

– Variation, Supplements or amendments to any of the above

What are the exemptions to these guidelines?

-The requirements of these guidelines do not cover the following groups of materials:

• Biotechnology or biological active substances 

• Immunological active substances

• Intermediates from process of APIs manufacturing

• Starting materials for APIs.

What is the application procedure for the issuance of permits for APIs?

The procedure for the control and issuance of permit for APIs is based on the following principles: 

-Understanding of the production and quality control for the manufacturer of the API

-Assessment of API data and information including changes and variation submitted by the API manufacturer/Applicant

-Assessment of manufacturing site(s) for compliance with GMP requirements for APIs

-Post marketing surveillance through randomized sampling and testing of APIs

-Handling complaints and recalls

-Local and external monitoring of co-agencies on complaints

What are the requirements for the documentation for Importation of APIs?

All applications for API import permit should be made through the Federal Government through the Single Trade Portal.

The following documents to support the application should be submitted through the Federal Government Single Trade E-Portal:

-An application (prepared by legal counsel) for permit to import drug substance(s) or Active Pharmaceutical Ingredient(s) should be made on the company’s letter-headed paper, signed by the Managing Director of the company or designated technical officer and addressed to: The Director-General, National Agency for Food and Drug Administration and Control (NAFDAC).

-The application letter should indicate the applicant’s address, location address of API source, the list of APIs and the purpose for which the API is required

– importation, distribution, sale, manufacturing of FPP etc. 

-Separate application letters should be submitted for different sites or sources of APIs.

– Applicants should duly complete an API request e-form on the portal under section of trader/client module to indicate the name of API and source of import (name and site address of API manufacturer), API grade e.g. USP or BP., size of unit pack e.g. 25kg bag, total amount requested in Kilogram (KG) per API, commodity code number as specified by the Nigeria Customs Service.

– An API manufactured from different sites, or with different synthesis route or of different salts should be treated as separate item when entering the list of APIs in the request form.

-The DMF (open and closed parts) or equivalent documentation (e.g. Common Technical Document modules 1 and 3) from the API Manufacturer(s) should be provided. This can be scanned and uploaded as an attachment to the application.

– The file size limit for scanned documents is 2 MB but there is no limit for the total size of all attachments. The file-size of an attachment can be reduced by scanning it in black and white instead of grayscale and with a scanning resolution of maximum of 300dpi.

– Note that as a result of file size limitation for scanned document attachments, DMFs (labeled) can also be submitted in a USB flash drive to NAFDAC.

-Current GMP Certificate or evidence of GMP compliance of the actual site of API manufacture and shipment to the applicant.

Inspection

– For FPP manufacturers and non-manufacturing importers, a risk-based approach is applied for GMP inspection of the FPP manufacturing site and importer’s warehouse respectively, and this will be done following successful assessment of DMF or equivalent documentation and payment of inspection fee.

-The modalities for inspection of the manufacturing site will be communicated to the applicant and a satisfactory report of such inspection or risk assessment in lieu of site inspection will be uploaded by NAFDAC inspectors on the e-portal for further processing of the application.

Approval

-A permit which authorizes the applicant to import the API is issued after a satisfactory review of DMF or equivalent documentation, satisfactory inspection of the manufacturing plant/warehouse and payment of appropriate API import permit fee.

What are the documentary requirements for an application for Permit to Import API by Educational, Research or Health Institutions?

The following documents are to be submitted online by other applicants (Educational, Research and Health Institutions) through the Federal Government Single Trade E-Portal: 

-Covering letter signed by head of institution

-Duly completed online API application e-form

-Certificate of Analysis of API from manufacturer

-Evidence of payment for API Import Permit

– A letter of undertaking stating that the API is strictly for academic or research purposes.

-API importation by this set of applicants should not exceed 25kg per item .

– Importation of APIs by educational, research and health institutions may not require site audit or ASMF assessment. 

-However, applicants in this category must pay the appropriate fees.

What do the guidelines say about post approval requests?

– Upon an initial approval, an applicant may request for additional APIs or additional quantities of approved items by following all the steps enumerated for processing a new application.

-DMF/ASMF submission will be required for additional items but not for additional quantities of approved items.

It should be noted that all approved API import permits must be utilized within the same calendar year of issuance.and neither constitutes legal advice nor a valid lawyer/client relationship.